The metabolic theory of cancer

What is cancer?

More than 150 years ago, Rudolf Virchow described cancer as “pathological cell growth.” However we still have no scientific consensus for the cause of this disease, which Hippocrates (460–370 BC), the father of medicine, is credited with naming the carcinoma.

We know that cancer cells have damaged DNA. We do not know why some cells with DNA damage go rogue.

Researchers have identified 10 characteristics that define cancer:

Sustained, self-sufficient, chronic proliferation
Insensitive to inhibitory signals that might stop their growth
Resist programmed cell death
Can multiply indefinitely (“limitless replicative potential”)
Stimulate the growth of blood vessels to supply nutrients
Invade local tissue and spread to distant sites (metastasis)
Exhibit abnormal metabolic pathways
Evade the immune system
Exhibit genome instability
Tumor-promoting inflammation.

There are competing theories as to why some cells become cancerous.

In 1953, James Watson and Francis Crick discovered the double-helix structure of the DNA molecule. That set the stage for what has become the dominant theory of cancer:

During the 1970s, scientists discovered oncogenes (genes that cause cells to grow out of control and become cancer cells), and tumour suppressor genes (normal genes that when damaged cause cells to grow out of control, which can lead to cancer).

This discovery led to the somatic mutation theory (SMT), which treats cancer as a disease of ‘genes gone awry.’

Conversely, the metabolic theory of cancer grew out of early 20th century research in Germany, research focused on abnormal energy generation. Dr. Otto Warburg (1883-1970) won the Nobel Prize for medicine in 1931 “for his discovery of the nature and mode of action of the respiratory enzyme.”

One common characteristic of all cancer cells is that they “over-utilize glucose even in the presence of oxygen, the ‘Warburg effect’.” Their energy metabolism is fundamentally different from healthy cells. Cancer cells generate energy through a less-effecient anaerobic process of fermentation.

Estimates are the 80-95% of cancer cells exhibit this behavior, which is why they can be detected with a positron emission tomography (PET) scan.

However Warburg’s theory that this abnormal energy production is the root cause of cancer has been rejected by the scientific establishment for most of its existence. Until now.

The NYTimes describes its revival thusly:

These researchers, typically molecular biologists by training, have turned to metabolism and the Warburg effect because their own research led each of them to the same conclusion: A number of the cancer-causing genes that have long been known for their role in cell division also regulate cells’ consumption of nutrients.

One prominent proponent is Thomas N. Seyfried, PhD, author of “Cancer as a Metabolic Disease: On the Origin, Management, and Prevention of Cancer” as well as several (open access) journal articles on the topic:

Rather than cancer being caused by broken DNA, in this theory the broken DNA is a byproduct “linked to abnormalities in the structure and function of the mitochondria.” Mitochondria are tiny structures that generate power for cells. Cancer cells have fewer, and more broken, mitochondria than healthy cells.

Travis Christofferson, author of Tripping over the Truth, The Metabolic Theory of Cancer, provides a readable historical context as he persuasively argues that the metabolic theory fits the data more logically and scientifically than the SMT.

There are sobering statistics to support his claims. Researchers in the Cancer Genome Atlas project have identified 10,000 genomic profiles and 10 million mutations associated with cancer. But “not a single mutational profile is reliably diagnostic for any kind of cancer,” Christofferson says.

Christofferson points out that when researchers, in the 1980s, transfered the nucleus of a cancer cell to normal cells with normal mitochondria, the cancer was suppressed. But the converse, transferring the nucleus of a normal cell to cancer cells, with their damaged mitochondria, had no affect on the cancer. This experiment drives home the point that the nucleus is not the driver of cancer behaviors; instead, it’s the cell’s abnormal mitochondria. Hence, metabolism-driven behavior.

Although cancer cells resist death, when starved of nutrients, they die.

Treatment may include ketogenic metabolic therapy (KMT), acknowledging that cancer cells can live only on glucose not fatty acids and ketones like normal cells. Research trials are in progress.

Again, the NYTimes from 2016:

Metabolism-centered therapies have produced some tantalizing successes. Agios Pharmaceuticals, a company co-founded by Thompson, is now testing a drug that treats cases of acute myelogenous leukemia that have been resistant to other therapies by inhibiting the mutated versions of the metabolic enzyme IDH 2. In clinical trials of the Agios drug, nearly 40 percent of patients who carry these mutations are experiencing at least partial remissions.

Researchers working in a lab run by Peter Pedersen, a professor of biochemistry at Johns Hopkins, discovered that a compound known as 3-bromopyruvate can block energy production in cancer cells and, at least in rats and rabbits, wipe out advanced liver cancer. (Trials of the drug have yet to begin.) At Penn, Dang and his colleagues are now trying to block multiple metabolic pathways at the same time. In mice, this two-pronged approach has been able to shrink some tumors without debilitating side effects. Dang says the hope is not necessarily to find a cure but rather to keep cancer at bay in a “smoldering quiet state,” much as patients treat their hypertension.

One of the most promising treatments is a generic drug, metformin, used to treat diabetes. For diabetic patients, metformin provides about a 30% reduction across the board in cancer risk. Even Watson, the father of DNA, takes metformin as a preventative.

Just as there are competing theories as to the cause of heart disease — dietary fat versus sugar — there are competing theories about cancer. But obesity is on track to surpass lung cancer as a preventable cancer risk, and we now know that the dietary fat fears of the late 20th century were, in the main, misplaced. Just as Warburg’s theories are coming ’round again, so is the John Yudkin (1910-1955) theory that sugar is poison.

Christofferson closes his book with information about dietary changes as well as medicinal cocktails. The Care Oncology Clinic in London is treating patients with four repurposed drugs: metformin, a statin, an anti-fungal, and doxycycline. All have correlations with reduced cancer risk and there is some evidence that they may work synergistically.